This invention relates to the chemotherapy of bacterial infections in mammalian subjects. More particularly it relates to penicillanoyloxylmethyl penicillanate 1,1,1', 1'-tetraoxide, a new chemical substance useful in the field of antibacterial chemotherapy.
One of the most well-known and widely used of the classes of antibacterial agents is the class known as the beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. One useful beta-lactamase inhibitor is penicillanic acid 1,1-dioxide, the compound of the formula I: ##STR1## West German Offenlegungsschrift No. 2,824,535 describes the preparation of penicillanic acid 1,1-dioxide, and methods for its use as a beta-lactamase inhibitor in combination with beta-lactam antibiotics.
My co-pending application Ser. No. 39,539, filed May 16, 1979 now U.S. Pat. No. 4,244,951, discloses compounds of the formula ##STR2## in which R.sup.1 is an acyl group of an organic carboxylic acid, especially an acyl group from a natural, biosynthetic or semisynthetic penicillin compound. In one method of preparing the compounds of formula II, a carboxylate salt of a penicillin compound is reacted with a compound of the formula ##STR3## wherein X is a good leaving group. Examples of X are chloro, bromo, iodo, alkylsulfonyloxy, phenylsulfonyloxy and tolylsulfonyloxy. Example 25 of application Ser. No. 39,539 now U.S. Pat. No. 4,244,951 specifically describes the preparation of the compound of formula III, wherein X is chloro, by reaction of the diisopropylethylamine salt of penicillanic acid 1,1-dioxide with chloroiodomethane. However this reaction also produces the compound of the formula ##STR4## and it has been found that the compound of formula IV acts as a bio-precursor of penicillanic acid 1,1-dioxide in mammalian, especially human, subjects.
Belgian Pat. No. 764,688, granted Mar. 23, 1971, and British Pat. No. 1,303,491, published Jan. 17, 1973, disclose: (a) certain 6'-acylaminopenicillanoyloxymethyl 6-acylaminopenicillanates; (b) certain 6'-acylaminopenicillanoyloxymethyl 6-aminopenicillanates; and (c) 6'-aminopenicillanoyloxymethyl 6-aminopenicillanate.